In the past several years immunoconjugates have been developed as an alternative therapeutic approach to treat malignancies. Immunoconjugates were originally composed of an antibody chemically conjugated to a plant or a bacterial toxin, a form that is known as an immunotoxin. The antibody binds to the antigen expressed on the target cell and the toxin is internalized causing cell death by arresting protein synthesis and inducing apoptosis (Brinkmann, U., Mol. Med. Today, 2:439-446 (1996)). More recently, genes encoding the antibody and the toxin have been fused and the immunotoxin expressed as a fusion protein.
A number of studies have been conducted on immunotoxins which use as the toxic moiety a bacterial toxin known as Pseudomonas exotoxin A (“PE”). Typically, the PE has been truncated or mutated to reduce its non-specific toxicity without destroying its toxicity to cells to which it is targeted by the targeting portion of the immunotoxin. Clinical trials are currently underway testing the use of PE-based immunotoxins as treatments for a variety of cancers.
Current PE-based immunotoxins are highly immunogenic. This has not proven to be a problem in the treatment of hematological malignancies, in which the ability of the immune system to mount a response is often compromised. Immunotoxins can typically be administered multiple times to patients with hematological malignancies. Patients with solid tumors, however, usually develop neutralizing antibodies to PE-based immunotoxins within weeks after the first administration. Since many protocols call for a three week period between administration of immunotoxins, the development of the antibodies during this period effectively means that, for solid tumors, usually only one administration can be made of a PE-based immunotoxin before the patient's antibodies render it ineffective. Even a single administration of a PE-based immunotoxin can be highly useful in reducing the patient's tumor burden, in eliminating smaller metastases, and in alleviating symptoms. Nonetheless, it would be desirable to have less antigenic forms of PE-based immunotoxins that would reduce patients' immunogenic responses.
The present invention satisfies these and other needs.